The present MERIT award continues the theme of understanding the activation and transformation by erbB family oncogenes and seeks to characterize the role of erbB2/HER/neu in prostate cancer biology. In the past grant period, significant progress has been made, which reveals that erbB2 in prostate cancer cells crosstalks not only with other erbB receptors, but also receptor for cytokine IL6. This interaction is functionally important, as inactivating erbB2 receptor leads to impaired IL6 induction of MAP kinase pathway and neuroendocrine differentiation (NED). This is the first time that erbB3 was found to be activated by a cytokine and that IL6, a potent stimulator, was found to induce NED of prostate cancer cells. NED of prostate cancers has been implicated in PCA progression and androgen independent state. Increasing evidence suggests that NE cells serve as paracrine source for the growth and migration of the surrounding tumor cells. Compared to other processes, the mechanisms of NED are understudied. Another discovery supported by this grant is the development of a tyrosine kinase display method which permits the identification of virtually all tyrosine kinases in a single PCR reaction and in a single gel. Dr. Kung therefore knows precisely all the tyrosine kinases expressed in a single PCA cell type. With this method, he uncovers a tyrosine kinase Etk in PCA which is critical in NED or PCA. The present proposal is based on the above three novel findings and intends to study: 1) the mechanisms involved in receptor cross talk between erbB2 and IL6 receptor and 2) the NED signal pathways mediated by erbB2 and Etk.